1. Field of the Invention
The present invention relates to a treatment of ocular hypertension with a synergistic combination comprising (a) a 13,14-dihydro-15-keto-20-loweralkylprostaglandin compound and (b) a polyoxyethylenesorbitan unsaturated higher aliphatic acid ester.
The compounds used as the component (a) in the present invention are prostaglandin analogues which can be obtained synthetically.
2. Information of Prior Art Prostaglandins (hereinafter, prostaglandins are referred to as PGs) are members of a class of organic carboxylic acid that are contained in human and most other mammalian tissues or organs and that exhibit a wide range of physiological activities. Naturally occurring PGs possess as a common structural feature the prostanoic acid skeleton: ##STR1## Some synthetic analogues have somewhat modified skeletons. The primary PGs are classified based on the structural feature of the five-membered cycle moiety into PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs and PGJs, and also on the presence or absence of unsaturation and oxidation in the chain moiety as:
Subscript 1--13,14-unsaturated-15-OH PA1 Subscript 2--5,6- and 13,14-diunsaturated-15-OH PA1 Subscript 3--5,6- 13,14- and 17,18-triunsaturated-15-OH PA1 (b) a polyoxyethylenesorbitan unsaturated higher aliphatic acid monoester PA1 (a) a 13,14-dihydro-15-keto-20-loweralkylprostaglandin or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof, and PA1 (b) a polyoxyethylenesorbitan unsaturated higher aliphatic acid monoester PA1 (a) a 13,14-dihydro-15-keto-20-loweralkylprostaglandin or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof, and PA1 (b) a polyoxyethylenesorbitan unsaturated higher aliphatic acid monoester
Further, PGFs are sub-classified according to the configuration of hydroxy group at position 9 into .alpha.(hydroxy group being in the alpha configuration) and .beta.(hydroxy group being in the beta configuration).
The fact that the above compounds under item (a) have ocular hypotensive activity has been known by Japanese Patent Publication No. A-108/1990. The above publication describes, on page 9, column 2, line 3 from bottom, that polysorbates can be used as the diluent for preparing nonaqueous solution or suspension containing the above mentioned compounds. The above description, however, only shows a possibility of using the polysorbates and does not show the fact that the activity of the component (a) is enhanced or side-effect of the same is suppressed. In addition, while compounds called polysorbates include polyoxyethylenesorbitan saturated aliphatic acid esters such as polysorbate 20 (polyoxyethylenesorbitan monolaurate), polysorbate 60 (polyoxyethylenesorbitan monostearate), polysorbate 65 (polyoxyethylenesorbitan tristearate) and polyoxyethylenesorbitan unsaturated aliphatic acid esters such as polysorbate 80 (polyoxyethylenesorbitan monooleate), the above mentioned description does not define that the aliphatic acid moiety in the polysorbates referred to therein is saturated or unsaturated. Therefore, it neither discloses specifically unsaturated esters and nor teaches that the unsaturated esters are superior to the saturated esters. Japanese Patent Publication No. A-317728/1988 describes that a formulation commercialized by Pharmacia contains PGF.sub.2 .alpha. isopropyl ester and polysorbate 80. However, PGF.sub.2 .alpha. is a primary PG having a double bond between positions 13 and 14 and a hydroxy group (in .alpha.-configuration) at position 15 in the main skeleton of 20 carbon atoms, while 13,14-dihydro-15-keto-20-loweralkyl-PGs, the component (a) are compounds having a saturated bond between positions 13 and 14 and an oxo group at position 15 in place of a hydroxy group, which has been believe to play an important role in the activities of the primary PGs, in the main skeleton of 21 or more carbon atoms by elongation of the omega chain. Therefore, the description shows neither co-use of the component (a) with polysorbate 80 nor enhanced activity or suppressed side-effect by the co-use.
As regards polysorbate 80, it has been known that polysorbate 80 inhibits the absorption of an active compound when both are intramusclarly administered (Chem. Pharm. Bull., 24, 2383-2390). It can be expected from this description that polysorbate 80 inhibits absorption of the component (a) when they are co-administered. Polysorbate 80 also known as an inducing agent of release of histamine (Agents and Actions, 16, 470-477). It can be expected from this description that polysorbate 80 increases irritation when it is administered with an active agent such as the component (a) in the present invention. In conclusion, while it may be expected that co-administration of the component (a) with polysorbate 80 decreases effect and increases side-effect, there is no grounds for believing that, contrary to the above expectation, the co-administration results in increase of effect and decrease of side-effect.
After an extensive study on the possibility that the effect of the component (a) in the present invention is improved by combining it with a variety of compounds, the present inventor has surprisingly discovered that the effect of the component (a) is significantly improved and side-effect is decreased by co-administration with a polyoxyethylenesorbitan unsaturated higher aliphatic acid monoester. Said discovery leads to the present invention.